WO2017012559A1 - 稠环嘧啶类化合物、中间体、其制备方法、组合物和应用 - Google Patents

稠环嘧啶类化合物、中间体、其制备方法、组合物和应用 Download PDF

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WO2017012559A1
WO2017012559A1 PCT/CN2016/090798 CN2016090798W WO2017012559A1 WO 2017012559 A1 WO2017012559 A1 WO 2017012559A1 CN 2016090798 W CN2016090798 W CN 2016090798W WO 2017012559 A1 WO2017012559 A1 WO 2017012559A1
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substituted
compound
group
alkyl group
heterocycloalkyl
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PCT/CN2016/090798
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English (en)
French (fr)
Chinese (zh)
Inventor
许祖盛
张农
汪廷汉
孙庆瑞
王玉光
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广州再极医药科技有限公司
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Priority to BR112018001209-2A priority Critical patent/BR112018001209B1/pt
Priority to CA2993096A priority patent/CA2993096C/en
Priority to US15/746,254 priority patent/US10494378B2/en
Priority to EP16827250.8A priority patent/EP3354653B1/en
Priority to JP2018503190A priority patent/JP6875372B2/ja
Priority to MX2018000945A priority patent/MX379383B/es
Priority to AU2016295594A priority patent/AU2016295594B2/en
Priority to KR1020187004890A priority patent/KR102591886B1/ko
Priority to RU2018103332A priority patent/RU2732576C2/ru
Priority to NZ739940A priority patent/NZ739940B2/en
Publication of WO2017012559A1 publication Critical patent/WO2017012559A1/zh

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Definitions

  • the present invention relates to a fused ring pyrimidine compound, an intermediate, a process for the preparation thereof, a composition and use.
  • JAK-STAT Japanese kinase-signal transducer and activator of transcription
  • JAK-STAT Japanese kinase-signal transducer and activator of transcription
  • This signaling pathway is relatively simple to transfer. It consists of three components, namely tyrosine kinase-related receptor, tyrosine kinase JAK and transcription factor STAT.
  • JAK Java Kinase
  • the intracellular molecule, JAK-catalyzed receptor is tyrosine phosphorylated, and the phosphate on the receptor molecule Is a recognition and binding site for a class of signaling molecules, STAT SH2.
  • Tyrosine phosphorylation occurs after STAT binds to receptors.
  • Tyrosine-phosphorylated STAT forms a dimer and enters the nucleus.
  • the dimeric STAT molecule directly affects the expression of related genes, thereby changing the proliferation or differentiation state of target cells.
  • the JAK-STAT pathway is widely present in various tissue cells in the body, especially for the differentiation, proliferation and anti-infection of lymphocyte lines, and is involved in the interaction and signal transduction of various inflammatory factors (Kiesseleva T. et al .J. Gene, 2002, 285, 1-24).
  • the abnormal activation of this pathway is closely related to many diseases. Finding and screening JAK inhibitors can help to further study the regulation mechanism of JAK-STAT, and provide new drugs and means for prevention and treatment of related diseases.
  • STAT3 is the focal point of the aggregation of multiple oncogenic tyrosine kinase signaling pathways such as EGFR, IL-6/JAK, and Src. It is activated in various tumor cells and tissues, such as breast cancer, ovarian cancer, and head and neck scales.
  • the JAK-STAT pathway inhibitor belongs to the PTK inhibitor, which is a member of the oncoprotein and proto-oncoprotein family. The cells play an important role in normal and abnormal proliferation. Tumors occur and grow inseparable from PTK. Therefore, JAK-STAT pathway inhibitors inhibit tumor growth by antagonizing PTK and have significant anti-tumor effects (Mora LB et al. J. Cancer Res. 2002, 62 (22) ), 6659-6666).
  • organ transplant rejection psoriasis, tissue and organ fibrosis, bronchial asthma, ischemic cardiomyopathy, heart failure, myocardial infarction, blood system diseases, and immune system diseases are all related to JAK-STAT signaling.
  • the pathway is closely related. This signal pathway is not only important for maintaining the normal physiological function of cells, but also plays an important role in regulating the occurrence and development of diseases.
  • the Fibroblast Growth Factor Receptor family belongs to a new class of receptor kinases that include four receptor subtypes encoded by four closely related genes (FGFR-1, 2, 3 And 4) and some isomeric molecules, which form a ternary complex with fibroblast growth factor (FGF) and heparan sulfate, which in turn initiates a series of signaling pathways involved in the regulation of physiological processes in the body.
  • FGFR has a wide range of physiological and pathological effects in the body: (1) embryonic development. Studies have shown that during embryonic development, FGFR signaling is critical for most organ development and embryonic pattern formation. (2) Cell division, migration and differentiation. FGFR stimulates cell proliferation and is involved in the regulation of cell transformation during pathology.
  • FMS-like tyrosine kinase 3 belongs to the type of receptor tyrosine kinase III (RTK III) family, which is composed of extracellular regions, intracellular regions and The transmembrane region is composed of three parts, which are first expressed in human hematopoietic stem cells.
  • FLT3 interacts with its ligand FL, stimulates or acts on stem cells, and is important for the growth and differentiation of stem cells.
  • FLT3 kinase has wild-type FLT3-WT and its major activating mutants FLT3-ITD and FLT3-D835Y.
  • FLT3 is mainly expressed in precursors of normal myeloid cells, but its abnormal expression is also found in a large proportion of acute myeloid leukemia (AML) cells.
  • AML acute myeloid leukemia
  • Src family kinase is a family of non-receptor tyrosine kinases including c-Src, LYN, FYN, LCK, HCK, FGR, BLK, YES and YRK, of which LYN kinase has LYN ⁇ and LYN ⁇ Both subtypes, LYN kinase and its two subtypes, are capable of causing similar intracellular tyrosine phosphorylation.
  • SFK can be divided into two subfamilies: one is c-Src, FYN, YES and FGR, which is widely expressed in different tissues; the other is LCK, BLK, LYN and HCK, which are closely related to hematopoietic cells.
  • SFK is linked to multiple signal transduction pathways in vivo and can be activated by growth factors, cytokines and immune cell receptors, G-protein coupled receptors, and integrin and other cell adhesion molecules, and then activates the corresponding signal transduction pathways. , causing a variety of physiological effects of cells.
  • the activity of SFK mainly includes cell morphology, cell movement, cell proliferation and survival regulation.
  • the technical problem to be solved by the present invention is to provide a fused ring pyrimidine compound, an intermediate, a preparation method, a composition and an application thereof, which are strong for Janus kinase (JAK), FGFR kinase, FLT3 kinase and Src family kinase. Inhibition.
  • JK Janus kinase
  • FGFR FGFR
  • FLT3 FLT3 kinase
  • Src family kinase Src family kinase.
  • the present invention provides a fused ring pyrimidine compound, a tautomer thereof, an enantiomer thereof, a diastereomer thereof, a pharmaceutically acceptable salt thereof, and a metabolism thereof, which are represented by Formula I. a product, a metabolic precursor thereof or a prodrug thereof;
  • P is selected from a hydrogen atom or a halogen atom
  • X is selected from CH or S
  • Y is selected from N or CR 5 ;
  • U is selected from a chemical bond or CH
  • V is selected from N or CH
  • W is selected from N or CR 6 ;
  • R 1 , R 2 , R 3 and R 6 are independently a hydrogen atom, a halogen atom, a halogen, a substituted or unsubstituted alkyl group, a cycloalkyl or heterocycloalkyl group; said R 7 , R 8 , R 9 , R 10 and R 15 are independently a hydrogen atom, a halogen atom, a halogen, a hydroxyl group, an amino group, a substituted or unsubstituted alkyl group, an alkane Oxyl, Or a heterocycloalkyl group; said R 11 is a hydrogen atom, a halogen atom or an alkyl group (preferably a C 1-4 alkyl group such as a methyl group); or, said R 6 , R 2 and The two atoms on the ring to which they are attached together form a "substituted or unsubstituted 5-7 membered carbon heterocycle"; alternatively, the R 6
  • R 4 is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, an alkoxy group, a cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group;
  • R 5 is a hydrogen atom, a halogen atom, a halogen or an alkyl group
  • the “substitution” described in the “substituted or unsubstituted alkyl group” is substituted by one or more of the following groups, when there are many In the case of a substituent, the substituents are the same or different: halogen (preferably fluorine), hydroxyl group, amino group, alkyl group (preferably C 1-10 alkyl group, more preferably C 1-4) An alkyl group, such as methyl), an alkoxy group (preferably a C 1-10 alkoxy group, more preferably a C 1-4 alkoxy group such as a methoxy group), And a heterocycloalkyl group (the heterocycloalkyl group may be bonded via a carbon atom or a hetero atom thereof and other groups; preferably "the hetero atom is oxygen and/or nitrogen, and the number of heteroatoms is 1-4" a heterocycloalkyl group having 3-8 carbon atoms", more preferably "the heterocycloalkyl group having 3-8 carbon atoms", more preferably "
  • the “substitution” described in the “substituted or unsubstituted alkyl group” is substituted by one or more of the following groups,
  • the substituents are the same or different: a halogen atom, a halogen (preferably fluorine), a hydroxyl group, an amino group, an alkyl group (preferably a C 1-10 alkyl group), more preferably Is a C 1-4 alkyl group, such as methyl), alkoxy (preferably a C 1-10 alkoxy group, more preferably a C 1-4 alkoxy group, such as a methoxy group) ,
  • a heterocycloalkyl group the heterocycloalkyl group may be bonded via a carbon atom or a hetero atom thereof and other groups; preferably "the hetero atom is oxygen and/or nitrogen, and the number of heteroatoms is 1-4" a
  • the "substitution" described in the "substituted or unsubstituted alkyl group” and the “substituted or unsubstituted heterocycloalkyl group” is substituted by one or more of the following groups, when present In the case of a plurality of substituents, the substituents are the same or different: a hydroxyl group, an alkyl group (preferably a C 1-4 alkyl group, more preferably a methyl group), Or a heterocycloalkyl group (the heterocycloalkyl group may be bonded via a carbon atom or a hetero atom thereto and other groups; preferably "the hetero atom is oxygen and/or nitrogen, and the number of heteroatoms is 1-4" a heterocycloalkyl group having 3 to 6 carbon atoms", more preferably Said R 14 is a hydrogen atom, an alkyl group (preferably a C 1-4 alkyl group, more preferably a methyl group), a methylo
  • substitution described in the "substituted or unsubstituted 5-7 membered heterocyclic ring” is one or more alkyl groups (preferably a C 1-4 alkyl group such as a methyl group, Substituted by ethyl, propyl, etc.).
  • the halogen is preferably fluorine or chlorine; and the alkyl group described in the “substituted or unsubstituted alkyl group” is preferably a C 1-4 alkyl group, more preferably a methyl group; the heterocycloalkyl group may be bonded via a carbon atom or a hetero atom thereto and other groups; the heterocycloalkyl group is preferably " The hetero atom is oxygen and/or nitrogen, the hetero atom number is 1-4 heterocycloalkyl groups having 3-8 carbon atoms, and more preferably "the hetero atom is oxygen and/or nitrogen, and the number of heteroatoms is 1. - 4 (for example 1 or 2) heterocycloalkyl group having 3 to 6 carbon atoms", most preferably
  • the halogen is preferably fluorine; and the alkyl group described in the “substituted or unsubstituted alkyl group” is preferably Is a C 1-10 alkyl group, more preferably a C 1-4 alkyl group, most preferably a methyl group, a tridecyl methyl group, an ethyl group, a propyl group or an isopropyl group; Preferred is a C 1-10 alkoxy group, more preferably a C 1-4 alkoxy group, most preferably a methoxy group; the heterocycloalkyl group may be passed through a carbon atom or a hetero atom Connecting with other groups; the heterocycloalkyl group is preferably "hetero atom is oxygen and/or nitrogen, and the number of hetero atoms is 1-4 heterocycloalkyl groups having 3-8 carbon atoms", More preferably, "the hetero atom
  • the alkyl group described in the "substituted or unsubstituted alkyl group” is preferably a C 1-4 alkyl group, more preferably a methyl group, an ethyl group, a propyl group or Isopropyl; the alkoxy group is preferably a C 1-4 alkoxy group; the heterocycloalkyl group described in the "substituted or unsubstituted heterocycloalkyl group” may pass through the carbon therein The atom or a hetero atom is bonded to another group; the heterocycloalkyl group described in the "substituted or unsubstituted heterocycloalkyl group” is preferably "the hetero atom is oxygen and/or nitrogen, and the number of hetero atoms 1-4, heterocycloalkyl groups having 3-8 carbon atoms", more preferably "heterotoms are oxygen or nitrogen, 1-2 heteroatoms, and 3-6 carbon atoms Cycloalky
  • the halogen is preferably fluorine; the alkyl group is preferably a C 1-4 alkyl group, more preferably a methyl group.
  • the "5-7 membered carbon heterocyclic ring" described in the "substituted or unsubstituted 5-7 membered carbon heterocyclic ring” is preferably "the hetero atom is oxygen and/or nitrogen, and the number of hetero atoms is 1-4, 5-7 membered carbon heterocycles having 2 to 6 carbon atoms, more preferably
  • Said compound I is preferably as shown in formula I-1 or I-2.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y, V, W and P are independently as described above.
  • the compound I-1 is preferably as shown in the formula I-1-1 or I-1-2.
  • M is CH 2 or O, and the definitions of R 1 , R 3 , R 4 , R 5 , P, V and W are independently as described above.
  • Said compound 1-2 is preferably as shown in formula I-2-1 or I-2-2.
  • R 1 , R 3 , R 4 , Y and P are independently as described above.
  • the Y is preferably CR 5 .
  • the R 5 is preferably a hydrogen atom or an alkyl group.
  • the W is preferably CR 6 .
  • the R 6 is preferably a hydrogen atom.
  • the R 6 , R 2 and two atoms on the ring to which they are attached together form a "substituted or unsubstituted 5-7 membered carbon heterocyclic ring".
  • the R 1 and R 2 are independently a hydrogen atom or
  • the R 1 or R 2 is a hydrogen atom.
  • the R 3 is preferably a hydrogen atom, Halogen or
  • the R 4 is preferably a "substituted or unsubstituted alkyl group" or a "substituted or unsubstituted heterocycloalkyl group”.
  • each of the above substituents is further preferably as follows:
  • the Y is preferably CR 5 .
  • the R 5 is preferably a hydrogen atom or an alkyl group.
  • the W is preferably CR 6 .
  • the R 6 is preferably a hydrogen atom.
  • the R 6 , R 2 and two atoms on the ring to which they are attached together form a "substituted or unsubstituted 5-7 membered carbon heterocyclic ring".
  • the R 1 and R 2 are independently a hydrogen atom or
  • the R 1 or R 2 is a hydrogen atom.
  • the R 3 is preferably a hydrogen atom, Halogen or
  • the R 4 is preferably a "substituted or unsubstituted alkyl group" or a "substituted or unsubstituted heterocycloalkyl group”.
  • each of the above substituents is further preferably as follows:
  • the X is preferably S.
  • the Y is preferably CR 5 .
  • the R 5 is preferably an alkyl group.
  • the U is preferably a chemical bond.
  • the W is preferably CR 6 .
  • the R 6 is preferably a hydrogen atom.
  • the R 6 , R 2 and two atoms on the ring to which they are attached together form a "substituted or unsubstituted 5-7 membered carbon heterocyclic ring".
  • the R 1 and R 2 are independently a hydrogen atom or
  • the R 1 or R 2 is a hydrogen atom.
  • the R 3 is preferably a hydrogen atom, Halogen or
  • the R 4 is preferably a "substituted or unsubstituted alkyl group" or a "substituted or unsubstituted heterocycloalkyl group”.
  • each of the above substituents is further preferably as follows:
  • the X is preferably S.
  • the Y is preferably CR 5 .
  • the R 5 is preferably an alkyl group.
  • the W is preferably CR 6 .
  • the R 6 is preferably a hydrogen atom.
  • the R 6 , R 2 and two atoms on the ring to which they are attached together form a "substituted or unsubstituted 5-7 membered carbon heterocyclic ring".
  • the R 1 and R 2 are independently a hydrogen atom or
  • the R 1 or R 2 is a hydrogen atom.
  • the R 3 is preferably a hydrogen atom or
  • the R 4 is preferably a "substituted or unsubstituted alkyl group" or a "substituted or unsubstituted heterocycloalkyl group".
  • the compound I described in the present invention is any of the following compounds:
  • the compound I involved in the present invention may exhibit tautomerism, structural isomerism and stereoisomerism.
  • the invention includes any tautomeric or structural or stereoisomeric forms thereof, and mixtures thereof, which have the ability to modulate kinase activity, and the ability is not limited to any one isoform or mixture thereof; the kinase preferably It is JAK, FGFR kinase, FLT3 kinase and Src family kinase.
  • the present invention is a fused ring pyrimidine compound of the formula I, a tautomer thereof, an enantiomer thereof, a diastereomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, and a metabolism thereof.
  • the isotopes of the atoms contained in the precursor or its prodrug are usually present in a variety of isotopic abundance distributions in nature.
  • a fused ring pyrimidine compound represented by Formula I a fused ring pyrimidine compound represented by Formula I, a tautomer thereof, an enantiomer thereof, a diastereomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof
  • One or more of the isotopes of the atoms contained in the metabolic precursor or the prodrug thereof may be optionally used, for example, 1 H is replaced by D, and the compound after the isotope substitution may be prepared by referring to the preparation method of the compound before replacement. And has the same biological activity as the compound before replacement.
  • the isotopes used alternatively may be present in nature or artificially produced.
  • the invention also provides the preparation method of the above compound I, which is any one of the methods 1-13,
  • Process 1 comprises the steps of: subjecting compound 1-a to a methylation reagent in the presence of a base, preferably potassium carbonate, in an organic solvent, preferably acetone, to yield a compound 1 may be; the conditions of the substitution reaction may be the conditions conventional for such reactions in the field;
  • Process 2 comprises the steps of: in an organic solvent, preferably n-butanol and/or N,N-dimethylformamide, in a catalyst (preferably p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate)
  • a catalyst preferably p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate
  • Compound II and compound VI are subjected to a substitution reaction in the presence of one or more of tris(dibenzylidenefluoreneacetone)dipalladium to obtain compound I;
  • the conditions of the substitution reaction may be Conventional conditions for such reactions in the art;
  • the catalyst is tris(dibenzylidenefluorenone)dipalladium, preferably, the reaction further comprises a base (preferably potassium carbonate) and a ligand. (preferably 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1
  • Process 3 comprises the steps of: under the protection of an inert gas, in an organic solvent, preferably one or more of 1,4-dioxane, toluene and N,N-dimethylformamide
  • an organic solvent preferably one or more of 1,4-dioxane, toluene and N,N-dimethylformamide
  • a palladium catalyst preferably [1,1'-bis(diphenylphosphino)ferrocene] Palladium chloride dichloromethane complex, palladium acetate, one or more of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride and tetrakis(triphenylphosphine)palladium
  • a coupling reaction is carried out to obtain a compound I; wherein A is Br or I; the conditions of the coupling reaction can be conventional conditions in the field;
  • the organic solvent is 1,4-dioxane
  • the reaction system may further comprise water
  • Process 4 comprises the steps of: compound 9-a and 2-(4- in the presence of a base, preferably diisopropylethylamine, in an organic solvent, preferably dichloromethane. Substituting a piperidinyl)-2-propanol to obtain a compound 9; the conditions of the substitution reaction may be conventional conditions in the field;
  • Process 5 comprises the steps of: subjecting compound 17-a and morpholine to a substitution reaction in the presence of a base (preferably potassium carbonate) in an organic solvent, preferably acetonitrile, to give compound 17 Substitution reaction
  • a base preferably potassium carbonate
  • organic solvent preferably acetonitrile
  • Process 6 comprises the steps of: subjecting compound 17-a and pyrrolidine to a substitution reaction in the presence of a base (preferably potassium carbonate) in an organic solvent, preferably acetonitrile, to give compound 18
  • a base preferably potassium carbonate
  • organic solvent preferably acetonitrile
  • Process 7 comprises the steps of: subjecting compound 17-a and N-methylpiperazine to a substitution reaction in the presence of a base, preferably potassium carbonate, in an organic solvent, preferably acetonitrile.
  • a base preferably potassium carbonate
  • an organic solvent preferably acetonitrile.
  • Compound 19 is sizable; the conditions of the substitution reaction may be the conditions conventional for such reactions in the art;
  • Process 8 comprises the steps of: in an organic solvent, preferably dichloromethane, in a base (preferably N,N-diisopropylethylamine), N-hydroxybenzotriazole and 1
  • a base preferably N,N-diisopropylethylamine
  • N-hydroxybenzotriazole preferably N,N-diisopropylethylamine
  • the compound 23-b and the azetidine are subjected to a condensation reaction in the presence of ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride to obtain a compound 23;
  • the conditions of the condensation reaction may be the conditions conventional for such reactions in the art;
  • Process 9 comprises the steps of: deprotecting compound IV in the presence of an acid (preferably trifluoroacetic acid) in an organic solvent, preferably dichloromethane, to provide compound I.
  • an acid preferably trifluoroacetic acid
  • an organic solvent preferably dichloromethane
  • Process 10 comprises the steps of: compound 31 and 2-halogen in an organic solvent, preferably N,N-dimethylformamide, in the presence of a base, preferably potassium carbonate.
  • the substitution reaction of ethanol is carried out to obtain the compound 34; the conditions of the substitution reaction may be the conditions conventional for the reaction in the field;
  • Process 11 comprises the steps of: in an organic solvent, preferably dichloromethane, in a base (preferably diisopropylethylamine), 1-hydroxybenzotriazole and 1-ethyl-( Conditions for the presence of 3-dimethylaminopropyl)carbodiimide hydrochloride
  • a base preferably diisopropylethylamine
  • 1-hydroxybenzotriazole and 1-ethyl-( Conditions for the presence of 3-dimethylaminopropyl)carbodiimide hydrochloride
  • the compound 32 and the 2-hydroxyacetic acid are subjected to a condensation reaction to obtain a compound 36; the conditions of the condensation reaction may be conventional conditions in the field;
  • Process 12 comprises the steps of: compound 40-a and dimethylamine, triacetyl boron in an organic solvent, preferably dichloroethane, in the presence of an acid, preferably acetic acid.
  • the sodium hydride is subjected to a reductive amination reaction to obtain a compound 40; the conditions of the reductive amination reaction may be conventional conditions for such a reaction in the field;
  • Process 13 comprises the steps of: subjecting compound 31 and ethyl chloroformate to condensation in an organic solvent, preferably dichloromethane, in the presence of a base, preferably triethylamine.
  • organic solvent preferably dichloromethane
  • a base preferably triethylamine.
  • Compound 50 is sizable; the conditions of the condensation reaction can be the conditions conventional for such reactions in the field;
  • the invention also provides a compound II having the structure as follows:
  • R 1 , R 2 , R 3 , X, Y, U, P, V and W are as defined above.
  • it is any of the following compounds:
  • the invention also provides a compound III having the structure as follows:
  • A is Br or I, and R 4 , X, Y, U and P are as defined above.
  • R 4 , X, Y, U and P are as defined above.
  • it is any of the following compounds:
  • the invention also provides a compound IV having the structure as follows:
  • R 1 , R 2 , R 3 , X, Y, U, V, W and P are as defined above.
  • it is any of the following compounds:
  • the invention also provides a compound V which is any of the following compounds:
  • the present invention also provides a fused ring pyrimidine compound as described above, a tautomer thereof, an enantiomer thereof, a diastereomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, and the like
  • a metabolic precursor or a prodrug thereof for the preparation of a medicament for the prevention, alleviation or treatment, immune system diseases, autoimmune diseases, cell proliferation diseases, allergic diseases and cardiovascular diseases
  • immune system diseases such as organ transplant rejection
  • the autoimmune diseases such as rheumatoid arthritis, psoriasis, Crohn's disease, multiple sclerosis, etc.
  • the cell proliferation diseases such as myelofibrosis, hematoma (such as leukemia, lymphoma, etc.), solid tumors (such as kidney cancer, liver cancer, stomach cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, thyroid cancer, Ovarian cancer, glioblastoma, skin cancer, melanoma, etc.; the allergic condition, such as bronchial asthma, etc.; the cardiovascular diseases, such as ischemic cardiomyopathy, heart failure, myocardial infarction Wait.
  • myelofibrosis such as leukemia, lymphoma, etc.
  • solid tumors such as kidney cancer, liver cancer, stomach cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, thyroid cancer, Ovarian cancer, glioblastoma, skin cancer, melanoma, etc.
  • the allergic condition such as bronchial asthma, etc.
  • the cardiovascular diseases such as ischemic cardiomyopathy, heart failure, myocardial infarction Wait.
  • the present invention also provides a fused ring pyrimidine compound as described above, a tautomer thereof, an enantiomer thereof, a diastereomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, and the like
  • a metabolic precursor or a prodrug thereof for the preparation of a medicament for inhibiting Janus kinase, FGFR kinase, FLT3 kinase and Src family kinase
  • said Janus kinase is preferably JAK1, JAK2 and JAK3 One or more
  • the FGFR kinase is preferably one or more of FGFR1, FGFR2 and FGFR3
  • the FLT3 kinase is preferably FLT3-WT, One or more of FLT3-ITD and FLT3-D835Y
  • said Src family kinase is preferably one or more of c-Src, Lyn, Fyn, Lck
  • the cell proliferation diseases such as myelofibrosis, hematoma (such as leukemia, lymphoma, etc.), solid tumors (such as kidney cancer, liver cancer, stomach cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, thyroid cancer, Ovarian cancer, glioblastoma, skin cancer, melanoma, etc.; the allergic condition, such as bronchial asthma, etc.; the cardiovascular diseases, such as ischemic cardiomyopathy, heart failure, myocardial infarction Wait.
  • myelofibrosis such as leukemia, lymphoma, etc.
  • solid tumors such as kidney cancer, liver cancer, stomach cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, thyroid cancer, Ovarian cancer, glioblastoma, skin cancer, melanoma, etc.
  • the allergic condition such as bronchial asthma, etc.
  • the cardiovascular diseases such as ischemic cardiomyopathy, heart failure, myocardial infarction Wait.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a fused ring pyrimidine compound, a tautomer thereof, an enantiomer thereof, a diastereomer thereof, and a pharmaceutically acceptable compound thereof as described above Salt, a metabolite thereof, a metabolic precursor thereof or a prodrug thereof, and a pharmaceutically acceptable carrier and/or diluent; preferably, said fused ring pyrimidine compound, which is mutually
  • the dose of the isomer, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its metabolite, its metabolic precursor or its prodrug is a therapeutically effective amount.
  • the pharmaceutical composition of the present invention may be in a form suitable for oral administration or in the form of a sterile injectable aqueous solution, and the oral or injectable composition may be prepared according to any method known in the art for preparing a pharmaceutical composition.
  • the pharmaceutical composition of the present invention may be formulated into a single dosage form, particularly a liposomal dosage form, in combination with one or more clinically used chemotherapeutic agents in any suitable ratio according to conventional methods in the art. Tumor disease.
  • alkyl refers to a branched and straight-chain saturated aliphatic hydrocarbon group comprising from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, 4 , 4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof and the like.
  • alicyclic or "cycloalkyl” (including when used alone or in another group) refers to a moiety comprising saturated or partially unsaturated (containing 1 or 2 double bonds, but none of the rings are fully conjugated)
  • the electron system comprises a 1-3 ring cyclic hydrocarbon group comprising a monocyclic alkyl group, a bicycloalkyl group and a tricycloalkyl group, which comprises 3-20 ring-forming carbons, preferably 3-10 Carbon, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane, cyclododecyl, cyclohexenyl and the like.
  • heterocycloalkyl refers to a 4-12 membered monocyclic ring containing from 1 to 4 heteroatoms such as one or more of nitrogen, oxygen and sulfur. Or a polycyclic group, wherein each ring may contain one or more pairs The bond, but none of the rings have a fully conjugated ⁇ -electron system.
  • Heterocycloalkyl groups within the scope of this definition include, but are not limited to, oxazoline, oxocyclobutyl, pyranyl, tetrahydropyranyl, azetidinyl, 1,4-dioxyl, Hexahydropyrazine, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydroimidazolyl, indanyl, dihydroisoxazole , dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrogen Tetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydr
  • the heterocycloalkyl group may be bonded to other groups via a carbon atom or a hetero atom therein.
  • any heterocycloalkyl ring can be fused to a cycloalkyl, aryl, heteroaryl or heterocycloalkyl ring to form a cyclo, bridge or spiro ring.
  • alkoxy (including when used alone and when included in other groups) denotes a cyclic or acyclic alkyl group having the number of carbon atoms attached through an oxygen bridge. Thus, “alkoxy” includes the definition of the above alkyl and cycloalkyl.
  • aryl refers to any stable monocyclic or bicyclic carbon ring which may be up to 7 atoms in each ring, at least one of which is an aromatic ring.
  • aryl unit include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. It will be understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the linkage is carried out through an aromatic ring.
  • arylhetero or “heteroaryl” (including when used alone and in other groups) denotes a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and Containing from 1 to 4 heteroatoms selected from O, N, and S.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, oxazolyl, porphyrin, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl , benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, Tetrahydroquinoline.
  • heteroaryl is also understood to include any nitrogen-containing heteroaryl N-oxide derivative.
  • heteroaryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or does not contain a hetero atom, it is understood that the linkage is carried out by an aromatic ring or by a hetero atom comprising a ring, respectively.
  • halogen means fluoro, chloro, bromo, iodo or quinone.
  • hydroxy means -OH.
  • amino means -NH 2 .
  • cyano means -CN.
  • acyl means It refers to a monovalent atomic group remaining after the organic or inorganic oxyacid is removed from the hydroxyl group.
  • R- may include definitions of the above terms.
  • “pharmaceutically acceptable salts” refers to conventional acid addition or base addition salts which retain the biological effectiveness and properties of Compound A, from suitable non-toxic organic or inorganic acids, or organic or inorganic bases. form.
  • the acid addition salt include those derived from inorganic acids and derived from organic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, said organic The acid is, for example, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, lactic acid, fumaric acid or the like.
  • base addition salts include salts derived from ammonium, potassium, sodium and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide.
  • Chemical modification of a pharmaceutical compound (i.e., a drug) to a salt is a technique well known to pharmacists to achieve improved physical and chemical stability, hygroscopicity, flowability, and solubility of the compound.
  • pharmaceutically acceptable in “pharmaceutically acceptable carrier and/or diluent” means that the subject to whom the particular compound is administered is pharmaceutically acceptable and substantially non-toxic. of.
  • the reagents and starting materials used in the present invention are commercially available.
  • a positive progressive effect of the present invention is that the compound has a strong inhibitory effect on Janus kinase (JAK), FGFR kinase, FLT3 kinase and Src family kinase.
  • JAK Janus kinase
  • FGFR FGFR
  • FLT3 FLT3 kinase
  • Src family kinase Src family kinase
  • the structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • the nuclear magnetic resonance spectrum was obtained by a Bruker Avance-500 instrument. Deuterated dimethyl sulfoxide, deuterated chloroform and deuterated methanol were used as solvents, tetramethyl.
  • Silane (TMS) is an internal standard. Mass spectra were obtained by liquid chromatography-mass spectrometry (LC-MS) coupled to Agilent Technologies 6110 using an ESI ion source.
  • the microwave reaction was carried out in an Explorer automatic microwave synthesizer manufactured by CEM Corporation of the United States.
  • the magnetron frequency was 2450 MHz and the continuous microwave output power was 300 W.
  • the instrument used for high performance liquid phase preparation is Gilson 281, and the preparation column used is Shimadazu Shim-Pack. PRC-ODS, 20x250mm, 15 ⁇ m.
  • 2,4-Dimethoxybenzeneboronic acid 43 mg, 0.23 mmol
  • compound 2-a 50 mg, 0.16 mmol
  • sodium carbonate 51 mg, 0.47 mmol
  • dioxane 0.5 mL
  • water Into 0.5 mL, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (13 mg, 0.02 mmol) was added. The reaction was carried out three times with nitrogen, and the reaction solution was subjected to microwave reaction at 90 ° C for 40 minutes.
  • the compound 3-methoxybenzyl alcohol (10 g, 72.4 mmol) was dissolved in a mixed solution of acetonitrile (250 mL) and water (250 mL), then sodium bromate (19.1 g, 127 mmol) and sodium bisulfite (13.2 g) , 127 mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature for 1.5 hours, then quenched with a saturated aqueous solution of sodium thiosulfate (250 mL), and then used. Extract with dichloromethane (200 mL x 3).
  • 1,4-Diazabicyclo[2.2.2]octane was added to a solution of the compound (S)-tetrahydrofuran-3-methanol (1 mL, 12.48 mmol) in dichloromethane (10 mL). 4.76 g, 42.43 mmol) and p-toluenesulfonyl chloride (3.09 g, 16.2 mmol). After the addition was completed, the reaction solution was warmed to room temperature and stirred for 1 hour. Further, p-toluenesulfonyl chloride (1 g, 5.25 mmol) was added, and the mixture was stirred at 28 ° C for 16 hours. The reaction mixture was diluted with methylene chloride (30 mL), EtOAc (EtOAc)EtOAc. Obtained oil 12-c (2.1 g, yield: 70%).
  • 2-methoxyphenylboronic acid 150 mg, 1 mmol
  • compound 1-c 380 mg, 1.5 mmol
  • [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride 36 mg, 0.05 Methyl acetate and 2M aqueous sodium carbonate (2 mL, 4 mmol) were dissolved in 1,4-dioxane (8 mL).
  • the reaction solution was purged three times with nitrogen to remove oxygen from the system, and then heated at 110 ° C for 6 hours.
  • the reaction was cooled to room temperature, diluted with ice water (100 mL), and then extracted with dichloromethane (100 mL ⁇ 3).
  • 3-Bromocatechol (1.88 g, 10 mmol) was added to a reaction mixture of N,N-dimethylformamide (10 mL) and potassium carbonate (2.76 mL, 20 mmol), then diiodomethane (5.4 g) 20 mmol) was added to the mixture and stirred at 60 ° C for 3 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) : 73%).
  • the compound 48-b (250 mg, 0.68 mmol) and the compound 32-c (181 mg, 0.68 mmol) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (281 mg, 2.37 mmol), 2- Dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (58 mg, 0.13 mmol) and tris(dibenzylideneacetone) dipalladium (136 mg, 0.24 mmol). Under nitrogen, heat to 110 ° C and stir for 16 hours.
  • the compound was dissolved in 100% DMSO, and the appropriate concentration gradient was diluted with water according to the experiment, and added to a 384-well plate.
  • JAK2 enzyme (Carna, Cat. No. 08-045, Lot. No. 07CBS-1927)
  • JAK3 enzyme (Carna, Cat. No. 08-046, Lot. No. 08CBS-0371) was diluted with the following buffer Optimum concentration: 50 mM HEPES, pH 7.5, 0.0015% Brij-35, 2 mM DTT.
  • JAK1 enzyme (Carna, Cat. No. 08-144, Lot. No. 11 CBS-0144D), diluted to the optimal concentration with the following buffer: 25 mM HEPES, pH 7.5, 0.01% Brij-35, 2 mM DTT, 0.01 M Triton . Transfer to a 384-well plate and incubate with the compound for a certain period of time.
  • 3.JAK2,3 substrate was diluted with the buffer to an optimum concentration: 50mM HEPES, pH 7.5,0.0015% Brij -35,10mM MgCl 2, ATP at Km.
  • the JAK1 substrate was diluted to the optimal concentration with the following buffer: 25 mM HEPES, pH 7.5, 0.01% Brij-35, 10 mM MgCl 2 , 0.01 M Triton, adenosine triphosphate at Km.
  • the reaction was started by adding a 384-well plate and reacted at 28 ° C for 1 hour.
  • the compound was dissolved in 100% DMSO, and the appropriate concentration gradient was diluted with water according to the experiment, and added to a 96-well plate.
  • FGFR1 enzyme (Carna, Cat. No. 08-133, Lot. No. 09 CBS-0989), FGFR2 enzyme (Carna, Cat. No. 08-134, Lot. No. 07 CBS-2468), JAK3 enzyme (Carna , Cat. No. 08-135, Lot. No. 06CBS-3177) was diluted to the optimal concentration with the following buffer: 50 mM HEPES, pH 7.5, 0.0015% Brij-35, 2 mM DTT. Transfer to 96-well plates and incubate with compound at 28 °C for a certain period of time.
  • the reaction was stopped by the addition of buffer solution 100 mM HEPES, pH 7.5, 0.0015% Brij-35, 0.2% Coating Reagent and 50 mM EDTA.
  • the compound was dissolved in 100% DMSO, and the appropriate concentration gradient was diluted with water according to the experiment, and added to a 96-well plate.
  • FLT3 enzyme (Carna, Cat. No. 08-154, Lot. No. 07CBS-2350), FLT3-ITD enzyme (Invitrogen, Cat. No. PV6191, Lot. No. 1753453), FLT3-D835Y enzyme (Invitrogen , Cat. No. PR7450A, Lot. No. 1629729C) was diluted to the optimal concentration with the following buffer: 50 mM HEPES, pH 7.5, 0.0015% Brij-35, 10 mM MgCl 2 , 2 mM DTT. Transfer to 96-well plates and incubate with compound at 28 °C for a certain period of time.
  • the reaction was stopped by the addition of buffer solution 100 mM HEPES, pH 7.5, 0.0015% Brij-35, 0.2% Coating Reagent and 50 mM EDTA.
  • the compound was dissolved in 100% DMSO, and the appropriate concentration gradient was diluted with water according to the experiment, and added to a 96-well plate.
  • the reaction was stopped by the addition of buffer solution 100 mM HEPES, pH 7.5, 0.0015% Brij-35, 0.2% Coating Reagent and 50 mM EDTA.

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PCT/CN2016/090798 2015-07-21 2016-07-21 稠环嘧啶类化合物、中间体、其制备方法、组合物和应用 WO2017012559A1 (zh)

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BR112018001209-2A BR112018001209B1 (pt) 2015-07-21 2016-07-21 Composto de pirimidina de anel fundido, intermediário, e método de preparação, composição e uso do mesmo
CA2993096A CA2993096C (en) 2015-07-21 2016-07-21 Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof
US15/746,254 US10494378B2 (en) 2015-07-21 2016-07-21 Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof
EP16827250.8A EP3354653B1 (en) 2015-07-21 2016-07-21 Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof
JP2018503190A JP6875372B2 (ja) 2015-07-21 2016-07-21 縮合環ピリミジン系化合物、中間体、その製造方法、組成物及び応用
MX2018000945A MX379383B (es) 2015-07-21 2016-07-21 Compuesto de pirimidina de anillo fusionado, intermediario y método de preparación, composición y uso del mismo.
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